We reported previously that interleukin-13 (IL-13) induces tyrosine phosphorylation/activation of Jak2 and Tyk2 kinases and Stats 1, 3, 5, and 6 in primary human monocytes. We recently revealed that p38 MAPK-mediated serine phosphorylation of both Stat1 and Stat3 is required for the induction of 15-lipoxygenase (15-LO) expression by IL-13. In this study, we present data indicating that another serine/threonine kinase, PKC␦, is also required for IL-13-induced 15-LO expression. PKC␦, a member of the novel protein kinase C (PKC) subclass, was rapidly phosphorylated and activated upon exposure to IL-13. Treatment of cells with rottlerin, a PKC␦ inhibitor, blocked IL-13-induced 15-LO mRNA and protein expression, whereas Go6976, an inhibitor of the conventional PKC subclass, had no inhibitory effects. Down-regulation of cellular PKC␦ protein levels by PKC␦-specific antisense oligodeoxyribonucleotides also inhibited 15-LO expression markedly. IL-13-induced 15-LO expression resulted in significant inhibition of synthesis of the potent chemotactic factor leukotriene B 4 , and that process was reversed by rottlerin, presumably through the blockage of PKC␦-dependent 15-LO expression. Furthermore, our data demonstrate that IL-13-mediated activation of PKC␦ and p38 MAPK are independent pathways, because inhibition of one kinase activity had no effect on the other, suggesting that the two pathways act in parallel to regulate the downstream targets necessary for 15-LO expression. Inhibition of PKC␦ activation by rottlerin also markedly attenuated IL-13-induced Stat3 DNA binding activity. Our findings indicate that PKC␦ plays an important role in regulating IL-13-induced 15-LO expression in human monocytes and subsequently modulates the inflammatory responses mediated by 15-LO products.Th2 lymphocytes secrete IL-4 1 and IL-13, which have the unique ability to induce the expression of the lipid-oxidizing enzyme 15-LO in primary human monocytes (1-3). To date, no monocytic cell lines have been shown to respond in a similar fashion. 15-LO dioxygenates polyenoic fatty acids to their corresponding hydroperoxide derivatives. These molecules are potent mediators of inflammatory responses and are found in atherosclerotic lesions. It is believed that 15-LO products play an important role in the pathogenesis of atherosclerosis and other inflammatory diseases (4 -7). In addition to its pro-inflammatory actions, 15-LO has also been shown to suppress the inflammatory responses by inhibiting the production of the potent chemotactic factor LTB 4 . This process has been observed in several cell types, including human monocytes (8 -10).Previously, we demonstrated that Jak2 and Tyk2 are upstream tyrosine kinases involved in regulating IL-13-induced expression of 15-LO (3). We have further defined the functional IL-13 receptor complex, the association of Jaks with the receptor constituents, and the tyrosine phosphorylation and activation of Stats in response to IL-13 (11). Tyrosine phosphorylation of Stat molecules facilitates the formation of di...